Targeting Neoantigens in Triple Negative Breast Cancer
针对三阴性乳腺癌的新抗原
基本信息
- 批准号:10675496
- 负责人:
- 金额:$ 62.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:4T1Adenovirus VectorAdjuvant ChemotherapyAdoptive Cell TransfersAftercareAlgorithmsBreast Cancer ModelBreast Cancer PatientCSF1 geneCSF1R geneCancer CenterClinicalClinical ResearchCommunicable DiseasesDNA VaccinesDataDiseaseEmbryoEnrollmentEpitopesEvaluationGenerationsHIV vaccineHistocompatibility Antigens Class IIHumanImmune responseImmunotherapyInflammatoryLymphoidMacrophageMalignant NeoplasmsModelingModernizationMusMyelogenousMyeloid CellsNeoadjuvant TherapyOutcomePatientsPeptide VaccinesPhase I Clinical TrialsPhenotypePopulationPre-Clinical ModelPropertyPublicationsRandomizedRecombinantsReportingSeriesSourceT cell responseTestingTissuesTumor ImmunityTumor PromotionTumor-associated macrophagesVaccinatedVaccinationVaccine TherapyVaccinesValidationanti-PD-L1antigen-specific T cellsarmcancer clinical trialcancer immunotherapydesignenzyme linked immunospot assayhigh dimensionalityimmune checkpoint blockadeimprovedinnovationinnovative technologiesmalignant breast neoplasmmanufacturemonocytemouse modelneoantigen vaccinationneoantigen vaccineneoantigensnext generation sequencingperipheral bloodphase I trialplasmid DNApreclinical studyprediction algorithmrecombinant adenovirusrecruitresponserestraintsingle-cell RNA sequencingtrial comparingtriple-negative invasive breast carcinomatumortumor growthtumor microenvironmentvaccine platformvaccine strategyvaccine trialvector vaccine
项目摘要
PROJECT SUMMARY/ABSTRACT
Neoantigens have been identified by us and others as important targets of immunotherapy in the context of
checkpoint blockade therapy, adoptive cell therapy, and vaccine therapy. We have recently initiated two phase
1 clinical trials of first generation neoantigen vaccines in breast cancer based on the neoantigen DNA vaccine
and synthetic long peptide vaccine platforms. In preclinical models, we have optimized sequencing and epitope
prediction algorithms for the identification and prioritization of neoantigens, and we have leveraged innovative
technologies (CyTOF, single cell RNA sequencing) to comprehensively interrogate the immune response to
neoantigen vaccination and other cancer immunotherapies. We propose to build on these observations by
performing a randomized phase 1 trial of neoantigen DNA vaccine alone vs. neoantigen DNA vaccine plus
anti-PD-L1, in patients with persistent triple negative breast cancer (TNBC) following neoadjuvant
chemotherapy. The overall hypothesis is that enhancing neoantigen-specific T cell responses can improve
clinical outcomes in TNBC. This hypothesis will be tested by completing the following aims:
Specific Aim 1. Test the hypothesis that neoantigen vaccines +/- anti-PD-L1 can induce and/or enhance
neoantigen-specific T cell responses. We have recently initiated a randomized phase 1 clinical trial of
neoantigen DNA vaccines +/- anti-PD-L1 in TNBC patients with persistent disease following neoadjuvant
chemotherapy. Next-generation sequencing and epitope prediction algorithms will be used to prioritize
neoantigens. Neoantigen DNA vaccines will be designed and manufactured in the GMP facility at SCC.
Specific Aim 2: Test the hypothesis that targeting tumor-associated macrophages (TAM) can enhance
neoantigen-specific T cell responses in TNBC. Both embryonically-derived tissue-resident TAM and
inflammatory monocyte-derived TAM restrain antitumor immunity in TNBC. We propose to combine
CSF1/CSF1R blockade with CCR2 inhibition to simultaneously target both sources of TAM in the context of
neoantigen vaccination in two mouse breast cancer models. The tumor microenvironment will be characterized
by CyTOF and single cell RNA sequencing.
Specific Aim 3: Test the hypothesis that a neoantigen simian Ad vector vaccine "prime" followed by a
neoantigen DNA vaccine "boost" can enhance the response to breast cancer neoantigens. We propose
a "prime/boost" strategy consisting of a simian recombinant Ad vaccine "prime," followed by a plasmid DNA
vaccine "boost." This "prime/boost" neoantigen vaccine strategy represents a state-of-the-art vaccine strategy
to more effectively induce antitumor immunity, and leverages expertise at WUSM within the fields of
neoantigen DNA vaccines and recombinant Ad vector vaccines. Photocleavable tetramer analysis, CyTOF,
and single cell RNA sequencing will be performed on neoantigen-specific T cells in the peripheral blood and
the tumor microenvironment to rigorously evaluate the neoantigen-specific T cell response to vaccination.
项目概要/摘要
我们和其他人已将新抗原确定为免疫治疗的重要靶标
检查点阻断疗法、过继细胞疗法和疫苗疗法。我们最近启动了两个阶段
1 基于新抗原DNA疫苗的第一代乳腺癌新抗原疫苗的临床试验
和合成长肽疫苗平台。在临床前模型中,我们优化了测序和表位
用于新抗原的识别和优先排序的预测算法,我们利用了创新的
技术(CyTOF,单细胞 RNA 测序)全面询问免疫反应
新抗原疫苗接种和其他癌症免疫疗法。我们建议在这些观察的基础上
单独进行新抗原 DNA 疫苗与新抗原 DNA 疫苗加疫苗的随机 1 期试验
抗 PD-L1,用于新辅助治疗后持续性三阴性乳腺癌 (TNBC) 患者
化疗。总体假设是增强新抗原特异性 T 细胞反应可以改善
TNBC 的临床结果。该假设将通过完成以下目标来检验:
具体目标 1. 检验新抗原疫苗 +/- 抗 PD-L1 可以诱导和/或增强的假设
新抗原特异性 T 细胞反应。我们最近启动了一项随机 1 期临床试验
新抗原 DNA 疫苗 +/- 抗 PD-L1 用于新辅助治疗后疾病持续存在的 TNBC 患者
化疗。将使用下一代测序和表位预测算法来确定优先级
新抗原。新抗原 DNA 疫苗将在 SCC 的 GMP 设施中设计和制造。
具体目标 2:检验靶向肿瘤相关巨噬细胞 (TAM) 可以增强的假设
TNBC 中的新抗原特异性 T 细胞反应。胚胎来源的组织驻留 TAM 和
炎性单核细胞来源的 TAM 抑制 TNBC 的抗肿瘤免疫。我们建议结合
CSF1/CSF1R 阻断与 CCR2 抑制同时靶向 TAM 的两种来源
在两种小鼠乳腺癌模型中进行新抗原疫苗接种。肿瘤微环境将被表征
通过 CyTOF 和单细胞 RNA 测序。
具体目标 3:检验以下假设:新抗原猿猴 Ad 载体疫苗“引发”,然后是
新抗原DNA疫苗“加强”可以增强对乳腺癌新抗原的反应。我们建议
“初免/加强”策略,由猿猴重组 Ad 疫苗“初免”和随后的质粒 DNA 组成
疫苗“增强”。这种“初免/加强”新抗原疫苗策略代表了最先进的疫苗策略
更有效地诱导抗肿瘤免疫,并利用 WUSM 在以下领域的专业知识
新抗原DNA疫苗和重组Ad载体疫苗。光裂解四聚体分析,CyTOF,
并对外周血中的新抗原特异性 T 细胞进行单细胞 RNA 测序,
肿瘤微环境来严格评估新抗原特异性 T 细胞对疫苗接种的反应。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Cancer-associated mutations reveal a novel role for EpCAM as an inhibitor of cathepsin-L and tumor cell invasion.
- DOI:10.1186/s12885-021-08239-z
- 发表时间:2021-05-12
- 期刊:
- 影响因子:3.8
- 作者:Sankpal NV;Brown TC;Fleming TP;Herndon JM;Amaravati AA;Loynd AN;Gillanders WE
- 通讯作者:Gillanders WE
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William E. Gillanders其他文献
Landscape of cancer associated EpCAM mutations: molecular modeling, predictive insights and impact on patient survival
- DOI:
10.1186/s12885-025-14455-8 - 发表时间:
2025-07-01 - 期刊:
- 影响因子:3.400
- 作者:
Priyanka S. Dhotare;Audrey C. Bochi-Layec;Timothy P. Fleming;William E. Gillanders;Ross M. Bremner;Kailas D. Sonawane;Narendra V. Sankpal - 通讯作者:
Narendra V. Sankpal
Molecular characteristics of isthmus papillary thyroid cancers: Supporting evidence for unfavorable clinical behavior
- DOI:
10.1016/j.amjsurg.2023.09.005 - 发表时间:
2024-02-01 - 期刊:
- 影响因子:
- 作者:
Eileen R. Smith;C. Corbin Frye;T.K. Pandian;William E. Gillanders;John A. Olson;Taylor C. Brown;Sina Jasim - 通讯作者:
Sina Jasim
Micrometastatic Disease and Isolated Tumor Cells as a Predictor for Additional Breast Cancer Axillary Metastatic Burden
- DOI:
10.1245/s10434-010-1255-1 - 发表时间:
2010-09-19 - 期刊:
- 影响因子:3.500
- 作者:
Amy Cyr;William E. Gillanders;Rebecca L. Aft;Timothy J. Eberlein;Feng Gao;Julie A. Margenthaler - 通讯作者:
Julie A. Margenthaler
Predictors of Primary Breast Abscesses and Recurrence
- DOI:
10.1007/s00268-009-0170-8 - 发表时间:
2009-08-08 - 期刊:
- 影响因子:2.500
- 作者:
Ankit Bharat;Feng Gao;Rebecca L. Aft;William E. Gillanders;Timothy J. Eberlein;Julie A. Margenthaler - 通讯作者:
Julie A. Margenthaler
Best practices for bioinformatic characterization of neoantigens for clinical utility
- DOI:
10.1186/s13073-019-0666-2 - 发表时间:
2019-08-28 - 期刊:
- 影响因子:11.200
- 作者:
Megan M. Richters;Huiming Xia;Katie M. Campbell;William E. Gillanders;Obi L. Griffith;Malachi Griffith - 通讯作者:
Malachi Griffith
William E. Gillanders的其他文献
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{{ truncateString('William E. Gillanders', 18)}}的其他基金
Molecular, Cellular, and Tissue Characterization Unit
分子、细胞和组织表征单元
- 批准号:
10904040 - 财政年份:2023
- 资助金额:
$ 62.51万 - 项目类别:
Targeting Neoantigens in Triple Negative Breast Cancer
针对三阴性乳腺癌的新抗原
- 批准号:
9980320 - 财政年份:2019
- 资助金额:
$ 62.51万 - 项目类别:
Targeting Neoantigens in Triple Negative Breast Cancer
针对三阴性乳腺癌的新抗原
- 批准号:
10458605 - 财政年份:2019
- 资助金额:
$ 62.51万 - 项目类别:
Targeting Neoantigens in Triple Negative Breast Cancer
针对三阴性乳腺癌的新抗原
- 批准号:
10224142 - 财政年份:2019
- 资助金额:
$ 62.51万 - 项目类别:
Molecular, Cellular, and Tissue Characterization Unit
分子、细胞和组织表征单元
- 批准号:
10461044 - 财政年份:2018
- 资助金额:
$ 62.51万 - 项目类别:
Molecular, Cellular, and Tissue Characterization Unit
分子、细胞和组织表征单元
- 批准号:
10242184 - 财政年份:2018
- 资助金额:
$ 62.51万 - 项目类别:
Peripheral Blood Molecular Staging of Breast Cancer
乳腺癌的外周血分子分期
- 批准号:
7923851 - 财政年份:2006
- 资助金额:
$ 62.51万 - 项目类别:
Peripheral Blood Molecular Staging of Breast Cancer
乳腺癌的外周血分子分期
- 批准号:
7285941 - 财政年份:2006
- 资助金额:
$ 62.51万 - 项目类别:
Peripheral Blood Molecular Staging of Breast Cancer
乳腺癌的外周血分子分期
- 批准号:
7480253 - 财政年份:2006
- 资助金额:
$ 62.51万 - 项目类别:
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